The candidate is an MD/PhD trained clinical neurologist whose career goal is to investigate genetic causes of susceptibility to traumatic brain injury (TBI), with emphasis in dementia and Alzheimer's disease (AD). The proposed period of mentored scientific training in the laboratory of Dr. David Holtzman at Washington University will allow the candidate develop the scientific skills to become an independent investigator. The central hypotheses that will be tested during the proposed project are as follows: 1) TBI causes increased production and/or decreased clearance of the amyloid-beta peptide (A-beta) in the brain. 2) The resulting increase in A-beta concentration contributes significantly to both acute cognitive impairment and the chronic pathology of AD in humans and in transgenic mice. 3) Blocking A-beta production or enhancing its clearance will reduce cognitive and pathological sequelae of TBI. 4) The increased vulnerability to TBI and increased risk of AD conferred by the apolipoprotein E e4 genotype (APOE4) occurs largely via apoE's effects on A-beta handling and metabolism. 5) Preventing TBI related changes in A-beta will lessen the adverse outcomes conferred by APOE4 after TBI. The candidate proposes to test these hypotheses using double transgenic mice that produce both apoE and a mutant amyloid precursor protein, and hence deposit A-beta in Alzheimer's disease-like pathological patterns. Experimental TBI will be performed on these mice in collaboration with Drs. Tracy McIntosh and Phil Bayly. Cognitive outcomes will be assessed using the Morris water maze and other behavioral tasks, and histological analysis of TBl-induced lesions and AD-like pathological changes will be made. Interventions will include administration of an anti-A-beta antibody that enhances A-beta clearance from the brain and a gamma secretase inhibitor that blocks A-beta production. Mechanistic studies of A-beta concentrations measured in brain homogenates and in vivo using microdialysis will be performed to gain insight into the underlying mechanisms involved. This work may lead to improved therapeutic options for patients with TBI in the future. [unreadable] [unreadable]